Background: Monoamine oxidases (MAO) are flavoenzymes that metabolize a range of brain neurotransmitters, whose dysregulation is closely associated with the development of various neurological disorders. This is why MAOs have been the central target in pharmacological interventions for neurodegeneration for more than 60 years. Still, existing drugs only address symptoms and not the cause of the disease, which underlines the need to develop more efficient inhibitors without adverse effects. Methods: Our drug design strategy relied on docking 25 organic scaffolds to MAO-B, which were extracted from the ChEMBL20 database with the highest cumulative counts of unique member compounds and bioactivity assays. The most promising candidates were substituted with the inactivating propargylamine group, while further affinity adjustment was made by its N-methylation. A total of 46 propargylamines were submitted to the docking and molecular dynamics simulations, while the best binders underwent mechanistic DFT analysis that confirmed the hydride abstraction mechanism of the covalent inhibition reaction. Results: We identified indole-2-propargylamine 4fH and indole-2-N-methylpropargylamine 4fMe as superior MAO-B binders over the clinical drugs rasagiline and selegiline. DFT calculations highlighted 4fMe as more potent over selegiline, evident in a reduced kinetic requirement (ΔΔG^‡ = −2.5 kcal mol⁻¹) and an improved reaction exergonicity (ΔΔG_R = −4.3 kcal mol⁻¹), together with its higher binding affinity, consistently determined by docking (ΔΔG_BIND = −0.1 kcal mol⁻¹) and MM-PBSA analysis (ΔΔG_BIND = −1.5 kcal mol⁻¹). Conclusions: Our findings strongly advocate 4fMe as an excellent drug candidate, whose synthesis and biological evaluation are highly recommended. Also, our results reveal the structural determinants that influenced the affinity and inhibition rates that should cooperate when designing further MAO inhibitors, which are of utmost significance and urgency with the increasing prevalence of brain diseases.

Surfactants are used in various washing applications with potential negative environmental and health impacts. The ion-pair 1,3-dioctadecyl-1H-1,2,3-triazol-3-ium-tetraphenylborate (DODTA–TPB) was used to fabricate the potentiometric sensor for the quantification of anionic surfactants. The computational analysis of the DODTA⁺–TPB⁻ adduct reveals a dynamic, thermodynamically favorable interaction driven primarily by hydrophobic C–H∙∙∙π contacts and the flexibility of the C-18 chains, rather than electrostatic or π–π stacking forces. These findings, supported by the MM-PBSA, RDF, and structural analyses, align with broader trends in molecular recognition and provide a foundation for designing advanced ion-pair-based sensors. The sensor showed advanced analytical properties to anionic surfactants with low interfering effects of selected anions. The response of the SDS was investigated in the range from 8.1 × 10⁻⁸ M to 1.0 × 10⁻² M, with a slope of −59.2 mV and a limit of detection (LOD) of 3.1 × 10⁻⁷ M; and DBS was in the range of 8.1 × 10⁻⁸ M to 2.5 × 10⁻³ M with a slope of −57.5 mV and an LOD of 5.9 × 10⁻⁷ M. The sensor was tested on potential interfering ions. Potentiometric titrations of technical-grade anionic surfactants had high recovery rates from 100.2 to 100.4%. The recovery test for spiked samples of surface waters was from 94.2 to 96.5%. The sensor was tested on commercial samples containing anionic surfactants, and the results were compared and showed a good agreement with the two-phase titration method.

The imidazo[4,5-b]pyridine scaffold, a versatile heterocyclic system, is renowned for its biological and chemical significance, yet its coordination chemistry with biologically relevant metal dications remains underexplored. This study investigates the proton and metal dication affinities of twelve tetracyclic organic molecules based on the imidazo[4,5-b]pyridine core, focusing on their interactions with Ca(II), Mg(II), Zn(II), and Cu(II). Employing a dual approach of electrospray ionization mass spectrometry (ESI-MS) and density functional theory (DFT) calculations, we characterized the formation, stability, and structural features of metal–ligand complexes. ESI-MS revealed distinct binding behaviors, with Cu(II) and Zn(II) forming stable mono- and dinuclear complexes, often accompanied by reduction processes (e.g., Cu(II) to Cu(I)), while Ca(II) and Mg(II) exhibited lower affinities. DFT analysis elucidated the electronic structures and thermodynamic stabilities, highlighting the imidazole nitrogen as the primary binding site and the influence of regioisomeric variations on affinity. Substituent effects were found to modulate binding strength, with electron-donating groups enhancing basicity and metal coordination. These findings provide a comprehensive understanding of the coordination chemistry of imidazo[4,5-b]pyridine derivatives, offering insights into their potential applications in metalloenzyme modulation, metal-ion sensing, and therapeutic chelation.

Background/Objectives: α-lipoic acid (ALA) shows therapeutic potential but faces poor aqueous solubility (BCS Class II), gastric instability, and low oral bioavailability (~30%). This work investigated the formulation of cyclodextrin (CD) inclusion complexes of ALA to overcome the aforementioned limitations and improve nutraceutical applications. Methods: Phase solubility studies in simulated gastric and intestinal fluids screened for optimal CD, followed by molecular dynamics simulations and MM-PBSA binding free energy calculations. Inclusion complexes of choice were prepared by grinding, spray-drying, and lyophilization, followed by solid-state characterization (DSC/XRPD/FTIR). Further analysis was performed using pH-shift dissolution (USP II), permeability (PermeaPad^®, Caco-2), and (photo)stability according to ICH. Results: Hydroxypropyl-β-cyclodextrin (HPβCD) emerged as the optimal host due to favorable complexation, as confirmed by phase solubility studies and supported by molecular modeling, which revealed a favorable balance between inclusion complex stability and pH-triggered drug release. Formulations based on spray-dried and lyophilized HPβCD–ALA complexes (HPβALA-sd and HPβALA-lyo), in which ALA was fully amorphized, achieved near-complete dissolution within five minutes under biorelevant pH-shift conditions. This performance markedly exceeded that of free ALA (approximately 66% dissolution at pH 7.4) while maintaining moderate permeability (Papp 8–9 × 10⁻⁶ cm/s). Storage stability was enhanced markedly (88–90% ALA retention after 6 months at 40 °C/75% RH vs. 36% for free ALA) while UV stability was not improved through CD-complexation, probably due to interaction of UV-VIS light with the exposed portion of ALA. Conclusions: Even though the permeability of ALA–CD inclusion complexes remained medium (Papp ~ 8–9 × 10⁻⁶ cm/s) and unaffected by complexation, a significantly improved dissolution profile indicates better expected bioavailability compared to pure ALA.

Three new phenanthridine peptide derivatives (19, 22, and 23) were synthesized to explore their potential as spectrophotometric probes for DNA and RNA. UV/Vis and circular dichroism (CD) spectra, mass spectroscopy, and computational analysis confirmed the presence of intramolecular interactions in all three compounds. Computational analysis revealed that compounds alternate between bent and open conformations, highlighting the latter’s crucial influence on successful polynucleotide recognition. Substituting one glycine with lysine in two regioisomers (22, 23) resulted in stronger binding interactions with DNA and RNA than for a compound containing two glycines (19), thus emphasizing the importance of lysine. The regioisomer with lysine closer to the phenanthridine ring (23) exhibited a dual and selective fluorimetric response with non-alternating AT and ATT polynucleotides and induction of triplex formation from the AT duplex. The best binding constant (K) with a value of 2.5 × 10⁷ M⁻¹ was obtained for the interaction with AT and ATT polynucleotides. Furthermore, apart from distinguishing between different types of ds-DNA and ds-RNA, the same compound could recognize GC-rich DNA through distinct induced CD signals.